Fluid for accommodating intraocular lenses

ABSTRACT

Fluids incorporated into intraocular lenses and their methods of use. In some embodiments the fluids are silicone oils, and in some embodiments they are used in accommodating intraocular lenses.

CROSS-REFERENCE

This application is a continuation of U.S. application Ser. No.13/033,474, filed Feb. 23, 2011, now U.S. Pat. No. 8,900,298, whichapplication claims the benefit of U.S. Provisional Patent ApplicationNo. 61/307,354, filed Feb. 23, 2010, the disclosures of which areincorporated herein by reference.

INCORPORATION BY REFERENCE

All publications and patent applications mentioned in this specificationare herein incorporated by reference to the same extent as if eachindividual publication or patent application was specifically andindividually indicated to be incorporated by reference.

BACKGROUND

Intraocular lenses (“IOL”) may comprise one or more fluids disposedtherein. For example, some accommodating IOLs use fluid movement withinthe IOL, or a change in fluid pressure within the IOL, to effect opticalpower change in the IOL. Exemplary accommodating IOLs that include afluid can be found in U.S. Pat. App. Pub. Nos. 2008/0306588, filed Jul.22, 2008, and 2008/0306587, filed Jul. 22, 2008, the disclosures ofwhich are incorporated herein by reference. Exemplary methods ofaccommodation in response to natural ciliary muscle movement are alsodescribed therein. For example, in the embodiment shown in FIGS. 3-5 inU.S. Pat. App. Pub. No. 2008/0306588, a fluid pressure increase in theoptic portion causes the shape of the anterior surface of the opticportion to change, thereby changing the power of the lens. Silicone oilis an example of a fluid that can be used in an IOL. In the embodimentshown, the peripheral portion is in fluid communication with the opticportion, allowing, for example, silicone oil to flow between the opticportion and the peripheral portion. The bulk material of the lensincludes anterior lens element 16, intermediate layer 18, and posteriorelement 22. The bulk material can also be considered to include thehaptic bulk material in the peripheral portion of the IOL.

When fluids such as silicone oil are used in an accommodatingintraocular lens, the fluid, over time, may tend to swell into the bulkmaterial. This can reduce the amount of silicone oil available to drivethe optical power change in the IOL. It is therefore desirable tominimize the amount of swelling into the bulk material. It may also beimportant to provide silicone oil that does not reduce the response timeof the accommodating IOL.

Some IOLs rely on, or can benefit from, a substantially uniformrefractive index throughout the IOL. It may therefore also be beneficialto provide silicone oil that has a refractive index that is as close tothe refractive index of the bulk material as possible.

Improved fluids (e.g., silicone oils), their methods of manufacture, andtheir methods of use in accommodating intraocular lenses are thereforeneeded.

SUMMARY

One aspect of the disclosure is a method of manufacturing silicone oilfor use in an intraocular lens, comprising purifying silicone oil to beused in an intraocular lens, wherein the silicone oil has apolydispersity index of less than about 1.5, and in some embodimentsless than about 1.3. The silicone oil can have a mean molecular weightof between about 5000 Daltons and about 6500 Daltons. In someembodiments there is no more than about 50 ppm of any low molecularweight component, such as components that have a molecular weight ofabout 1000 Daltons or less, in the silicone oil to be used in theintraocular lens. In some embodiments the method includes controllingthe refractive index of the silicone oil to be between about 1.47 andabout 1.49. In some embodiments purification step is a supercritical CO₂extraction, while in some embodiments it is a wiped-film extraction. Thepurification step substantially prevents the silicone oil from swellingin a bulk polymeric material of the intraocular lens. In someembodiments the silicone oil comprises diphenyl siloxane and dimethylsiloxane, and in some particular embodiments there is about 20% diphenylsiloxane and about 80% dimethyl siloxane.

One aspect of the disclosure is a method of manufacturing silicone oilfor use in an intraocular lens, comprising synthesizing silicone oil tobe used in an intraocular lens, wherein the silicone oil has apolydispersity index of less than about 1.5. The synthesis can be aliving polymerization synthesis. The method also includes a purificationstep after the synthesis step, which can be, for example, asupercritical CO₂ extraction or a wiped-film purification step. In someembodiments the silicone oil has a mean molecular weight of betweenabout 5000 Daltons and about 6500 Daltons. In some embodiments there isno more than about 50 ppm of any low molecular weight component in thesilicone oil. In some embodiments the viscosity of the silicone oil isless than about 1000 cSt at about 25° C.

One aspect of the disclosure is a method of manufacturing silicone oilfor use in an intraocular lens, comprising purifying silicone oil to beused in an intraocular lens, wherein the silicone oil has a meanmolecular weight between about 5000 Daltons and about 6500 Daltons. Thesilicone oil can have a polydispersity index of less than about 1.5. Insome embodiments there is no more than about 50 ppm of any low molecularweight component in the silicone oil. The manufactured silicone oil isadapted to avoid swelling in a bulk polymeric material of theintraocular lens. The silicone oil can comprise diphenyl siloxane anddimethyl siloxane.

One aspect of the disclosure is a method of manufacturing an intraocularlens, comprising providing a silicone oil that has been purified to havea polydispersity index of less than about 1.5; and assembling a bulkpolymer material and the silicone oil to form an intraocular lens. Theassembling step can comprise advancing the silicone oil into a fluidchamber within the bulk material of the intraocular lens. The siliconeoil can have been purified to have a mean molecular weight between about5000 Daltons and about 6500 Daltons. The silicone oil can have beenpurified such that there is no more than 50 ppm of any component thathas a molecular weight of about 1000 Daltons or less. In someembodiments the silicone oil has been substantially index-matched to atleast a portion of the bulk material.

One aspect of the disclosure is a method of using an intraocular lens:comprising creating an opening in the eye; and implanting in a posteriorchamber of an eye an intraocular lens comprising silicone oil purifiedto have a polydispersity index of less than about 1.5.

One aspect of the disclosure is silicone oil adapted to be used in anintraocular lens, wherein the silicone oil has been purified and has apolydispersity index less than about 1.5. The silicone oil can comprisediphenyl siloxane and dimethyl siloxane, and in some embodiments thesilicone oil comprises about 20 mol % diphenyl siloxane and about 80 mol% dimethyl siloxane. The silicone oil can have a mean molecular weightbetween about 5000 Daltons and about 6500 Daltons, and there are no morethan 50 ppm of any component that has a molecular weight of about 1000Daltons or less. In some embodiments the silicone oil has a viscosity ofless than about 1000 cSt at about 25° C. The refractive index can bebetween about 1.47 and about 1.49.

One aspect of the disclosure is silicone oil adapted to be used in anintraocular lens, wherein the silicone oil has been synthesized and hasa polydispersity index less than about 1.5.

One aspect of the disclosure is an accommodating intraocular lenscomprising a bulk polymeric material and silicone oil that has apolydispersity index less than about 1.5. The silicone oil can have anindex of refraction between about 1.47 and about 1.49. The silicone oilcan comprise diphenyl siloxane and dimethyl siloxane. The silicone oilcan have a mean molecular weight number average of between about 5000Daltons to about 6500 Daltons. The viscosity of the oil can be less thanabout 1000 cSt at about 25° C. In some embodiments there is no more than50 ppm of any component that has a molecular weight of about 1000Daltons or less.

DETAILED DESCRIPTION

The disclosure herein generally relates to fluid, such as silicone oil,that is used in an intraocular lens. In some embodiments the siliconeoil is used in an accommodating intraocular lens that uses fluidmovement to effect optical power change in the IOL. The silicone oilcan, however, be used in non-accommodating intraocular lenses as well.

Accommodating IOLs can utilize the eye's natural ciliary musclemovements to provide accommodation in the IOL. For example, someaccommodating IOLs are implanted within a patient's capsular bag (afterthe native lens has been removed) and respond to capsular bag reshapingto change the power of the lens. Some IOLs are designed to be implantedoutside of the lens capsule and accommodate in other ways. Whatever themethod of accommodation, silicone oil disposed within an accommodatingIOL can be adapted to be moved within the IOL in response to the eye'snatural movement in order to change the lens power. Properties of thesilicone oil can therefore affect the accommodative response time of theIOL. The selected silicone oil therefore does not undesirably hinder theresponse time of the IOL.

When silicone oil is used in accommodating IOL with a bulk material suchas a polymeric material, some of the oil components can pass into thebulk material, causing the bulk material to swell. The selected siliconeoil or oils therefore avoids the undesirable swelling of the bulkpolymer. Exemplary polymeric materials that can be used for the bulkmaterial of the IOL can be found in U.S. application Ser. No.12/177,720, filed Jul. 22, 2008, and in U.S. application Ser. No.12/034,942, filed Feb. 21, 2008, the disclosures of which areincorporated herein by reference.

One characteristic of silicone oil that helps ensure an adequateresponse and avoids undesirable swelling is the polydispersity index(“PDI”) of the silicone oil to be used in the IOL. PDI is generally ameasure of the distribution of molecular mass in a given sample. Arelatively low PDI indicates a relatively narrow range of molecularweights. The silicone oils described herein have a PDI less than about1.5, and more particularly less than or equal to about 1.3.

A second characteristic of the silicone oil that helps ensure anadequate response and avoids undesirable swelling is the mean molecularweight of the silicone oil. When high concentrations of relatively lowmolecular weight components are present in the silicone oil, a greaternumber of low molecular weight components pass into the bulk material ofthe IOL causing the swelling of the bulk material. To avoid undesirableswelling, the concentration of relatively low molecular weightcomponents should be minimized. By reducing the concentration ofrelatively low molecular weight components and maintaining a highconcentration of relatively high molecular weight components, fewer lowmolecular weight components will pass into the bulk polymer material,reducing the amount of swelling that occurs in the bulk material.

The PDI of the silicone oil and the mean molecular weight of the oil arerelated—by lowering the PDI of the silicone oil while providing siliconeoil with high concentrations of relatively high molecular weightcomponents and low concentrations of low molecular weight components,the response of the IOL is maintained (by providing a silicone oil withsuitable viscosity) and undesirable swelling is avoided. Additionally,providing silicone oil with a low PDI and very low concentrations ofsmall molecular weight components means that the silicone oil has amolecular weight just large enough to avoid swelling of the polymer.

In some embodiments silicone oil is provided that has a mean molecularweight between about 5000 and about 6500 Daltons, which is large enoughto substantially avoid swelling of the bulk polymeric material. This ispreferable to the alternative, which is using a higher molecular weightsilicone oil which has inherently fewer small molecule componentsbecause almost all molecules comprising it are large. High molecularweight silicone oils can have a correspondingly high viscosity, whichcan reduce the response time of the accommodating IOL.

The silicone oils described herein have a very low concentration ofrelatively low molecular weight components. The very low molecularweight components are present in an amount less than about 200 ppm ofeach component, and in some embodiments less than about 100 ppm. In someparticular embodiments the very low molecular weight components arepresent in an amount less than about 50 ppm.

The relatively low molecular weight components include those less thanor equal to about 1000 Daltons. For example, in some embodiments theconcentration of components less than or equal to about 1000 Daltons isnot more than about 50 ppm.

In one particular embodiment, silicone oil is provided in which no morethan 20% of the total silicone by weight is comprised of componentsbelow about 4000 Daltons; no more than 10% of the total polymer fluid byweight is comprised of components below 3000 Daltons; and no more than50 ppm of any components below 1000 Daltons.

The estimated molecular weights and polydispersities described hereinare relative to polystyrene molecular weights standards.

The silicone oil generally needs to be designed in such a way as toavoid adverse interactions with the surrounding bulk IOL material, suchas swelling, fogging, dissolving or reacting with the material (e.g.,poly acrylate) in some IOLs. The degree of solubility of the siliconeoil in the bulk material is dependent on the chemical structure andmolecular weight distribution of the silicone oil. Other parameters thatinfluence this interaction are the composition and properties of thebulk material such as homogeneity, chemical structure, hydrophobicity,modulus, and crosslink density.

The viscosity of the silicone oil also generally needs to be defined andminimized because, in embodiments in which the fluid-drivenaccommodating IOL operates dynamically, the IOL must have an appropriateresponse time. In some embodiments the viscosity of the silicone oil isless than about 1000 cSt at 25° C.

In some embodiments the silicone oil is comprised of diphenyl siloxaneand dimethyl siloxane. In some embodiments the oil is a diphenylsiloxane and dimethyl siloxane copolymer with about 20 mol % diphenylsiloxane and about 80 mol % dimethyl siloxane.

In some IOLs it may be desirable to avoid creating an optical interfacebetween the bulk material of the IOL and the silicone oil within theIOL. This can be done by index-matching the silicone oil to the bulkmaterial of the IOL, which in some embodiments is a polymeric material.“Index-matching” as used herein refers to minimizing the opticalinterface between first and second media. For example, index-matchingsilicone oil and a polymeric material refers to attempting to eliminatean optical interface therebetween, and “substantially the same” refersto indexes of refraction that, even though they may be slightlydifferent, are intended to be as close as possible to minimize thedifference in refractive indexes.

In some embodiments in which the silicone oil is index-matched to thebulk polymeric material, the refractive index of silicone oil is betweenabout 1.47 and about 1.53, and in some embodiments is between about 1.47and about 1.49.

In some embodiments the silicone oil must be able to be filtered throughan about 0.7 micron filter. In some embodiments the percent volatilesare less than about 0.2%. In some embodiments the silicone oil has achromatic dispersion less than or equal to about 0.035 refractive indexunits in the visible range of 400 nm to 750 nm at 35° C. In someembodiments the silicone oil components are fully miscible with eachother without evidence of phase separation (i.e. cloudiness orsuspensions). In some embodiments the silicone oil has greater than 85%transmittance in the range of 400 nm to 1100 nm for about a 1 cm thickfluid sample.

In addition, the silicone oil should be clear, colorless, have less thanabout 10 ppm heavy metals and other insoluble inorganics contaminants,and have substantially no silanols.

Synthesis

The molecular weight, polydispersity, and in some instances therefractive index of the silicone oil can be controlled by the way inwhich the silicone oil is synthesized and purified. The viscosity of theoil is related to the molecular weight of the oil, the polydispersity ofthe oil, and the architecture of the bulk polymer, all of which areinfluenced by the synthesis and purification of the polymer. However, atarget viscosity can not be arbitrarily selected independent of thetarget molecular weight, polydispersity, composition, and architectureof the silicone oil. A general class of polymer synthesis reactionsknown as “living polymerization reactions” can offer the degree ofcontrol necessary to assist in meeting some of the design requirementsfor a silicone oil.

The term “living polymerization” implies a polymerization reaction thatdoes not have a significant number of chain terminating or chaintransferring side reactions. The absence of side reactions allows livingpolymerizations to be used to synthesize a variety of materials thatwould be otherwise difficult to prepare. This class of polymerizationreactions can be used to prepare polymers with a variety of 1)architectures—including linear, “star”, and “comb” polymers; 2)compositions—homopolymers, random copolymers, block copolymers, andgraft copolymers; and 3) functionalized polymers—one and two endfunctional polymers, and side functional polymers. This class ofpolymerization reactions can be used to prepare polymers that often havea narrow molecular weight distribution and at a variety of molecularweights. As a result, living polymerizations are often employed whenpolymers with specific structures and compositions are needed. Forexample, a polymer with a large molecular weight distribution can beconsidered to be a mixture of a large number of compounds, and theproperties of the material are some function of that distribution.Polymers that have a small molecular weight distribution, however, ascan result from a living polymerization, can be considered a “purer”sample, with properties that are better defined.

Anionic and cationic living polymerizations have been described in theart. More recently, radical living polymerizations may have beendeveloped. In an example of an anionic synthetic route, the use of alkyllithium compounds in the ring opening polymerization ofcyclotrisiloxanes appears to be a “living” polymerization, allowing forthe degree of control needed to make the silicone oils described above.By varying the ratio of phenyl containing cyclotrisiloxanes to methylonly containing cyclotrisiloxanes (that is, preparing a random blockcopolymer), the refractive index of the silicone oil can be variedbetween the refractive index of either pure homopolymer alone (i.e.,between pure diphenyl polysiloxane and pure dimethyl polysiloxane).

As another example, the refractive index of the silicone oil can bevaried by varying the ratio of a tetramethyl-diphenyl-cyclotrisiloxaneto hexamethyl cyclotrisiloxanes. Varying this ratio can providedifferent refractive indexes between about 1.40 and about 1.54,including those between about 1.47 and 1.49.

As mentioned above, a living polymerization also offers the advantage ofbeing able to prepare polymer products of a targeted molecular weight.This can be accomplished by varying the monomer to initiator ratioduring the polymerization reaction, an application which can be appliedto the preparation of silicone oils of a specified formula weight.

The feature of a narrow range of molecular weight products is also anadvantage that can be realized in the preparation of silicone oilsbecause fewer low molecular weight oligomers are made during thepolymerization reaction. The smaller quantity of the low molecularweight materials prepared minimizes the amount of purification thatneeds to occur later to remove them from the higher molecular weightproducts. For example, when fewer low molecular weight oligomers aremade during the polymerization reaction, it is easier to extract the lowmolecular weight materials when purifying the synthesized silicone oilusing a supercritical CO₂ extraction (described below), resulting inhigher yields of the desired product.

While the viscosity of a polymer is not directly related to the way inwhich the polymer is prepared, a living polymerization can also be usedto indirectly modify this feature of the product polymer. Livingpolymerizations can be used to make polymer architectures that would bedifficult to accomplish using other synthetic strategies. For example,“comb” polymers, “star” polymers, and other branched structures can beprepared, which, even though they have a very similar chemicalcomposition to a “linear” polymer, may have different physicalproperties (e.g., viscosity), because of the different physicalgeometries those structures have. Preparation of a highly branchedsilicone oil may yield a product which has a significantly lowerviscosity than a silicone oil with the same molecular weight but alinear structure.

Silicone oils can also be prepared using other synthetic strategies suchas the base catalyzed ring opening of cyclotrisiloxanes, and thecondensation of dialkyldichloro silanes with water. These syntheticstrategies can also prepare silicone oils with many of thecharacteristics described above, but can require more effort onpurification.

Purification

Silicon oils can be purified in a variety of ways. Wiped filmevaporation can be used to remove low molecular weight compounds thathave a high boiling point. The silicone oil product may, however, bediscolored on excessive heating when using wiped film evaporation.

Supercritical CO₂ extraction is one exemplary purification method thatcan be used to selectively remove fractions of silicone oil based onmolecular weight and based on chemical affinity. Supercritical CO₂extraction to purify silicone oils to produce silicone vitreoretinaltamponades is described in U.S. Pat. No. 7,276,619, the entiredisclosure of which is incorporated by reference herein. These oils arenot used for IOLs, are particularly not in fluid-drive accommodatingIOLs. Pressure, temperature, rate of extraction conditions, and the useof co-eluting solvents such as, for example, acetone, can be varied toyield fractions that have a narrow molecular weight distribution (i.e.,a low PDI). A mixture can be separated in such a way as to strip thevery low and very high molecular fractions from a sample achieving thedesired molecular weight. Because supercritical extraction conditionscan be varied to get separation based on chemical affinity, thispurification method can also be used to achieve a desired refractiveindex. Supercritical CO₂ extraction can therefore be used to produce asilicone oil with, for example, an index of refraction substantially thesame as a bulk polymer to be used in an intraocular lens (e.g., in afluid-driven accommodating intraocular lens).

Tables 1-3 provide data from exemplary supercritical CO₂ extractions ofsample silicone oils.

TABLE 1 Silicone Oil Sample Time at 85 C. (Hrs) % Weight Change 1 40443.15 2 404 24.48 3 404 11.11 4 404 6.15 6 404 1.67 7 404 13.25

TABLE 2 Silicone Oil Sample Mean RI 1 1.477792 2 1.48604 3 1.487633 41.49067 5 1.494362 6 1.498737 7 1.492858

TABLE 3 Silicone Oil Sample Viscosity (cP) at 25.0 C. stdev 1 38.40 1.202 87.12 1.37 3 175.68 2.01

Similarly, preparative scale size exclusion chromatography is analternative method to fractionate a polymer sample into molecular weightcomponents. Fractional precipitation of the silicone oil may also beused to separate components of the product polymer.

Removal of silicone oil components that dissolve into the bulk IOLmaterial over time (e.g., during storage) may also be accomplished byexposing the silicone oil to bulk quantities of the IOL material, orother materials that have been selected for that purpose. On storagewith an appropriate material, the components of the silicone oil thatdissolve into the bulk IOL polymeric material may be removed byadjusting the ratio of silicone oil to polymer adsorbent so thatsufficiently low levels of those materials remain in the oil.

While silicone oils used in accommodating IOLs are primary describedherein, it is possible to use any of the silicone oils in anon-accommodating IOL. For example, a non-accommodating IOL can have arelatively rigid outer polymeric shell surrounding a silicone oil core.Swelling of the bulk polymeric material would still need to be takeninto consideration, and hence the methods of manufacturing desiredsilicone oil described herein could be utilized.

What is claimed is:
 1. An accommodating intraocular lens comprising afluid chamber, and a silicone oil disposed in the fluid chamber, whereinthe silicone oil comprises diphenyl siloxane and dimethyl siloxane thatare fully miscible with each other, and wherein the refractive index ofthe silicone oil is substantially the same as the refractive index of abulk material of the accommodating intraocular lens, wherein thesilicone oil has a chromatic dispersion less than or equal to about0.035 refractive index units in the visible range of 400 nm to 750 nm.2. An accommodating intraocular lens comprising a fluid chamber, and asilicone oil disposed in the fluid chamber, wherein the silicone oilcomprises diphenyl siloxane and dimethyl siloxane that are fullymiscible with each other, and wherein the refractive index of thesilicone oil is substantially the same as the refractive index of a bulkmaterial of the accommodating intraocular lens, wherein the silicone oilhas greater than 85% transmittance in the range of 400 nm to 1100 nm foran approximately 1 cm thick fluid sample of the silicone oil.
 3. Anaccommodating intraocular lens comprising a fluid chamber, and asilicone oil disposed in the fluid chamber, wherein the silicone oilcomprises no more than 50 ppm of any component that has a molecularweight of 1000 Daltons or less, and wherein no more than 20 wt % of thesilicone oil is comprised of components below 4000 Daltons.
 4. Anaccommodating intraocular lens comprising a fluid chamber, and asilicone oil disposed in the fluid chamber, wherein the silicone oilcomprises no more than 50 ppm of any component that has a molecularweight of 1000 Daltons or less, and wherein no more than 10 wt % of thesilicone oil is comprised of components below 3000 Daltons.